한국발생생물학회지:발생과생식 (Development and Reproduction)

  • 제22권2호
  • /
  • Pages.133-142
  • /
  • 2018
  • /
  • 2465-9525(pISSN)
  • /
  • 2465-9541(eISSN)
한국발생생물학회 (The Korean Society of Developmental Biology)
권호 표지
DOI QR코드

DOI QR Code

Combination of BEZ235 and Metformin Has Synergistic Effect on Cell Viability in Colorectal Cancer Cells

  • Kim, Taewan (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Kim, Taehyung (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Choi, Soonyoung (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Ko, Hyeran (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Park, Deokbae (Dept. of Histology, Jeju National University School of Medicine) ;
  • Lee, Youngki (Dept. of Histology, Jeju National University School of Medicine)
  • 투고 : 2018.05.30
  • 심사 : 2018.06.14
  • 발행 : 2018.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Patients with type II diabetes mellitus are more susceptible to colorectal cancer (CRC) incidence than non-diabetics. The anti-diabetic drug metformin is most commonly prescribed for the treatment of this disease and has recently shown antitumor effect in preclinical studies. The aberrant mutational activation in the components of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathway is very frequently observed in CRC. We previously reported that metformin inhibits the phosphorylation of ERK and BEZ235, a dual inhibitor of PI3K and mTOR, has anti-tumor activity against HCT15 CRC cells harboring mutations of KRAS and PIK3CA. Therefore, we hypothesized that simultaneous inhibition of two pathways by combining metformin with BEZ235 could be more effective in the suppression of proliferation than single agent treatment in HCT15 CRC cells. Here, we investigated the combinatory effect of metformin and BEZ235 on the cell survival in HCT15 CRC cells. Our study shows that both of the two signaling pathways can be blocked by this combinational strategy: metformin suppressed both pathways by inhibiting the phosphorylation of ERK, 4E-BP1 and S6, and BEZ235 suppressed PI3K/AKT/mTOR pathway by reducing the phosphorylation of 4E-BP1 and S6. This combination treatment synergistically reduced cell viability. The combination index (CI) values ranged from 0.44 to 0.88, indicating synergism for the combination. These results offer a preclinical rationale for the potential therapeutic option for the treatment of CRC.

키워드

참고문헌

  1. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626-1634. https://doi.org/10.1200/JCO.2007.14.7116
  2. Andreyeb HJN, Norman AR, Cunningham D, Oates J, Clarke PA (1998) Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. J Natl Cancer Inst 90:675-684. https://doi.org/10.1093/jnci/90.9.675
  3. Bennouna J, Lang I, Valladares-Ayerbes M, Boer K, Adenis A, Escudero P, Kim TY, Pover GM, Morris CD, Douillard JY (2011) A phase II, open-label, randomized study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs 29:1021-1028. https://doi.org/10.1007/s10637-010-9392-8
  4. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643-2648. https://doi.org/10.1158/0008-5472.CAN-06-4158
  5. Britten CB (2013) PI3K and MEK inhibitor combinations: Examining the evidence in selected tumor types. Cancer Chemother Pharmacol 71:1395-1409. https://doi.org/10.1007/s00280-013-2121-1
  6. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67:6745-6752. https://doi.org/10.1158/0008-5472.CAN-06-4447
  7. Chou TC, Talalay P (1981) Generalized equations for the analysis of inhibitions of Michaelis-Menton and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem 115:207-216.
  8. De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N (2012) The RAS/RAF/MEK/ERK and the PI3K/AKT signaling pathways: Role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets 16(sup2):S17-S27.
  9. Garrett CR, Hassalbo HM, Bhadkamkar NA, Wen S, Baladandayuthapani V, Kee BK, Eng C, Hassan MM (2012) Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br J Cancer 106:1374-1378. https://doi.org/10.1038/bjc.2012.71
  10. Gong J, Cho M, Fakih M (2016) RAS and BRAF in metastatic colorectal cancer management. J Gastrointest Oncol 7:687-704. https://doi.org/10.21037/jgo.2016.06.12
  11. Griss T, Vincent EE, Egnatchik R, Chen J, Ma EH, Faubert B, Viollet B, DeBerardinis RJ, Jones RG (2015) Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. Plos Biol 13:e1002309. https://doi.org/10.1371/journal.pbio.1002309
  12. Hsieh SC, Tsai JP, Yang SF, Tang MJ, Hsieh YH (2014) Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated $NF-{\kappa}B$-dependent pathway that reduces uPA and MMP-9 expression. Amino Acids 46:2809-2822. https://doi.org/10.1007/s00726-014-1838-4
  13. Iliopoulos D, Hirsch HA, Struhl K (2011) Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 71:3196-3201. https://doi.org/10.1158/0008-5472.CAN-10-3471
  14. Larsson SC, Orsini N, Wolk A (2005) Diabetes mellitus and risk of colorectal cancer: A meta-analysis. J Natl Cancer Inst 97:1679-1687. https://doi.org/10.1093/jnci/dji375
  15. Lee J, Park D, Lee YK (2017) Metformin synergistically potentiates the antitumor effects of imatinib in colorectal cancer cells. Dev Reprod 21:139-150. https://doi.org/10.12717/DR.2017.21.2.139
  16. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasix G, Penna C, Ducreux M, Rougier P, Penault-LIorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995. https://doi.org/10.1158/0008-5472.CAN-06-0191
  17. Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627-644. https://doi.org/10.1038/nrd2926
  18. Ma J, Guo Y, Chen S, Zhong C, Xue Y, Zhang Y, Lai X, Wei Y, Yu S, Zhang J, Liu W (2014) Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma. BMC Cancer 14:172-182. https://doi.org/10.1186/1471-2407-14-172
  19. MacKenzie T, Zens MS, Ferrara A, Schned A, Karagas MR (2011) Diabetes and risk of bladder cancer: Evidence from a case-control study in New Zealand. Cancer 117:1552-1556. https://doi.org/10.1002/cncr.25641
  20. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EWT, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA (2007) Roles of RAF/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773:1263-1284. https://doi.org/10.1016/j.bbamcr.2006.10.001
  21. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA (2010) Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res 3:1066-1076. https://doi.org/10.1158/1940-6207.CAPR-10-0055
  22. Mendoza MC, Er EE, Blenis J (2011) The RAS-ERK and PI3K-mTOR pathways: Cross-talk and compensation. Trends Biochem Sci 36:320-327. https://doi.org/10.1016/j.tibs.2011.03.006
  23. Mihaylova MM, Shaw RJ (2011) The AMPK signaling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016-1023. https://doi.org/10.1038/ncb2329
  24. Mohammed A, Janakiram NB, Brewer M, Ritchie RL, Marya A, Lightfoot S, Vernon ES, Rao CV (2013) Antidiabetic drug Metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl Oncol 6:649-659. https://doi.org/10.1593/tlo.13556
  25. Nangia-Makker P, Yu Y, Vasudevan A, Farhana L, Rajendra SG, Levi E, Majumdar APN (2014) Metformin: A potential therapeutic agent for recurrent colon cancer. PLoS One 9:e84369. https://doi.org/10.1371/journal.pone.0084369
  26. Niehr F, Euw E, Attar N, Guo D, Matsunaga D, Sazegar H, Ng C, Glaspy JA, Recio JA, Lo RS, Mischel PS, Comin-Andix B, Ribas A (2011) Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med 9:76-88. https://doi.org/10.1186/1479-5876-9-76
  27. Oh I, Cho H, Lee Y, Cheon M, Park D, Lee Y (2016) Blockage of autophagy rescues the dual PI3K/mTOR inhibitor BEZ235-induced growth inhibition of colorectal cancer cells. Dev Reprod 20:1-10. https://doi.org/10.12717/DR.2016.20.1.001
  28. Posch C, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, Kim C, Peng L, Dimon MT, Phillips T, Daud AI, McCalmont TH, LeBoit PE, Ortiz-Urda S (2013) Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Natl Acad Sci USA 110:4015-4020. https://doi.org/10.1073/pnas.1216013110
  29. Quinn BJ, Kitagawa H, Memmot RM, Gills JJ, Dennis PA (2013) Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab 24:469-480. https://doi.org/10.1016/j.tem.2013.05.004
  30. Santarpia L, Lippman SM, El-Naggar AK (2012) Targeting of the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets 16:103-119. https://doi.org/10.1517/14728222.2011.645805
  31. Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, Gunn S, Smetzer L, Mays TA, Kaiser B, Wick MJ, Alvarez C, Cavazos A, Mangold GL, Patnaik A (2012) The clinical effect of the dualtargeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res 18:2316-2325. https://doi.org/10.1158/1078-0432.CCR-11-2381
  32. Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, Jemal A (2017) Colorectal cancer statistics, 2017. CA Cancer J Clin 67:177-193. https://doi.org/10.3322/caac.21395
  33. Tseng CH (2012) Diabetes, metformin use, and colon cancer: A population-based cohort study in Taiwan. Eur J Endocrinol 167:409-416. https://doi.org/10.1530/EJE-12-0369
  34. Zhang HH, Guo XL (2016) Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemother Pharmacol 78:13-26. https://doi.org/10.1007/s00280-016-3037-3